tbuckley/cabot-search huggingface dataset:
Covid vaccines: Canada to dispose of 13.6 million AstraZeneca doses owing to lack of demand
Authors: Owen Dyer
Journal: BMJ (2022)

<h3>Objectives:</h3> To determine interobserver variability between an emergency medicine consultant and nurse practitioners for the use of the Wells score in the assessment of deep vein thrombosis (DVT) in the emergency department. <h3>Methods:</h3> A prospective cohort study was undertaken in a population of 100 cases of suspected DVT. The Wells score reading from the consultant was compared with the reading of the nurse practitioners. Consultant and nurses were blinded to each other’s assessments. The nurse practitioners were trained in interpreting the Wells score by assessing 100 patients together with the consultant before the start of the study. <h3>Results:</h3> Consultant and nurse practitioner assessments resulted in the same final Wells score in 81% of cases (simple agreement), with a kappa score of 0.74 (95% CI 0.63 to 0.84). If the nurse practitioner score had been followed in preference to the consultant assessment, this would have resulted in eight patients being assessed in a lower risk algorithm (8%). <h3>Conclusion:</h3> There is good interobserver agreement between consultant and nurse practitioners for the use of the Wells score as part of a DVT assessment service within the emergency department. Pretest scoring is pivotal to integrated strategies for the exclusion of DVT. The Wells score is a robust and reliable tool for pretest scoring in the emergency department regardless of the grade of the assessor, provided there is adequate training in its use.
Correlations between Clinical and Histopathologic Characteristics in Idiopathic Epiretinal Membrane
Authors: Lei-Chi Wang, Wen-Jung Lo, Ya-Yun Huang, Yu-Bai Chou, An-Fei Li, Shih-Jen Chen, Teh-Ying Chou, Tai-Chi Lin
Journal: Ophthalmology (2022)
Efficient Correction of Oncogenic <i>KRAS</i> and <i>TP53</i> Mutations through CRISPR Base Editing
Authors: Shady Sayed, Olga A. Sidorova, Alexander Hennig, Martina Augsburg, Catherine P. Cortés Vesga, Moustafa Abohawya, Lukas T. Schmitt, Duran Sürün, Daniel E. Stange, Jovan Mircetic, Frank Buchholz
Journal: Cancer Research (2022)

Abstract KRAS is the most frequently mutated oncogene in human cancer, and its activating mutations represent long-sought therapeutic targets. Programmable nucleases, particularly the CRISPR-Cas9 system, provide an attractive tool for genetically targeting KRAS mutations in cancer cells. Here, we show that cleavage of a panel of KRAS driver mutations suppresses growth in various human cancer cell lines, revealing their dependence on mutant KRAS. However, analysis of the remaining cell population after long-term Cas9 expression unmasked the occurence of oncogenic KRAS escape variants that were resistant to Cas9-cleavage. In contrast, the use of an adenine base editor to correct oncogenic KRAS mutations progressively depleted the targeted cells without the appearance of escape variants and allowed efficient and simultaneous correction of a cancer-associated TP53 mutation. Oncogenic KRAS and TP53 base editing was possible in patient-derived cancer organoids, suggesting that base editor approaches to correct oncogenic mutations could be developed for functional interrogation of vulnerabilities in a personalized manner for future precision oncology applications. Significance: Repairing KRAS mutations with base editors can be used for providing a better understanding of RAS biology and may lay the foundation for improved treatments for KRAS-mutant cancers.
Therapy-related clonal cytopenia as a precursor to therapy-related myeloid neoplasms
Authors: Mithun Vinod Shah, Abhishek A. Mangaonkar, Kebede H. Begna, Hassan B. Alkhateeb, Patricia Greipp, Ahmad Nanaa, Michelle A. Elliott, William J. Hogan, Mark R. Litzow, Kristen McCullough, Ayalew Tefferi, Naseema Gangat, Mrinal M. Patnaik, Aref Al-Kali, Rong He, Dong Chen
Journal: Blood Cancer Journal (2022)

Abstract Therapy-related myeloid neoplasms (t-MN) are aggressive leukemia that develops as a complication of prior exposure to DNA-damaging agents. Clonal cytopenia of undetermined significance (CCUS) is a precursor of de novo myeloid neoplasms. Characteristics of CCUS that develop following cytotoxic therapies (therapy-related clonal cytopenia, t-CC) and outcomes following t-CC have not been described. We identified 33 patients with t-CC and compared to a cohort of the WHO-defined t-MN ( n = 309). t-CC had a distinct genetic and cytogenetic profile: pathogenic variants (PV) in TET2 and SRSF2 were enriched in t-CC, whereas TP53 PV was more common in t-MN. Ten (30%) t-CC patients developed a subsequent t-MN, with a cumulative incidence of 13%, 23%, and 50% at 6 months, 1, and 5 years, respectively. At t-MN progression, 44% of evaluable patients had identifiable clonal evolution. The median survival following t-CC was significantly superior compared all t-MN phenotype including t-MDS with &lt;5% bone marrow blasts (124.5 vs. 16.3 months, P &lt; 0.001) respectively. The presence of cytogenetic abnormality and the absence of variants in DNMT3A , TET2 , or ASXL1 ( DTA -genes) were associated with a higher likelihood of developing a subsequent t-MN and an inferior survival. We describe a putative precursor entity of t-MN with distinct features and outcomes.
Role of dietary fiber in promoting immune health—An <scp>EAACI</scp> position paper
Authors: Carina Venter, Rosan W. Meyer, Matthew Greenhawt, Isabella Pali‐Schöll, Bright Nwaru, Caroline Roduit, Eva Untersmayr, Karine Adel‐Patient, Ioana Agache, Carlo Agostoni, Cezmi A. Akdis, Mary Feeney, Karin Hoffmann‐Sommergruber, Nonhlanhla Lunjani, Kate Grimshaw, Imke Reese, Peter K. Smith, Milena Sokolowska, Emilia Vassilopoulou, Berber Vlieg‐Boerstra, Shriya Amara, Jens Walter, Liam O'Mahony
Journal: Allergy (2022)

Abstract Microbial metabolism of specific dietary components, such as fiber, contributes to the sophisticated inter‐kingdom dialogue in the gut that maintains a stable environment with important beneficial physiological, metabolic, and immunological effects on the host. Historical changes in fiber intake may be contributing to the increase of allergic and hypersensitivity disorders as fiber‐derived metabolites are evolutionarily hardwired into the molecular circuitry governing immune cell decision‐making processes. In this review, we highlight the importance of fiber as a dietary ingredient, its effects on the microbiome, its effects on immune regulation, the importance of appropriate timing of intervention to target any potential window of opportunity, and potential mechanisms for dietary fibers in the prevention and management of allergic diseases. In addition, we review the human studies examining fiber or prebiotic interventions on asthma and respiratory outcomes, allergic rhinitis, atopic dermatitis, and overall risk of atopic disorders. While exposures, interventions, and outcomes were too heterogeneous for meta‐analysis, there is significant potential for using fiber in targeted manipulations of the gut microbiome and its metabolic functions in promoting immune health.
The Cerebellar Cortex
Authors: Court Hull, Wade G. Regehr
Journal: Annual Review of Neuroscience (2022)

The cerebellar cortex is an important system for relating neural circuits and learning. Its promise reflects the longstanding idea that it contains simple, repeated circuit modules with only a few cell types and a single plasticity mechanism that mediates learning according to classical Marr-Albus models. However, emerging data have revealed surprising diversity in neuron types, synaptic connections, and plasticity mechanisms, both locally and regionally within the cerebellar cortex. In light of these findings, it is not surprising that attempts to generate a holistic model of cerebellar learning across different behaviors have not been successful. While the cerebellum remains an ideal system for linking neuronal function with behavior, it is necessary to update the cerebellar circuit framework to achieve its great promise. In this review, we highlight recent advances in our understanding of cerebellar-cortical cell types, synaptic connections, signaling mechanisms, and forms of plasticity that enrich cerebellar processing.
The pleiotropic effects of α‐thalassemia on <scp>HbSS</scp> and <scp>HbSC</scp> sickle cell disease: Reduced erythrocyte cation co‐transport activity, serum erythropoietin, and transfusion burden, do not translate into increased survival
Authors: John N. Brewin, Amina Nardo‐Marino, Sara Stuart‐Smith, Sara El Hoss, Anke Hanneman, John Strouboulis, Stephan Menzel, John S. Gibson, David C. Rees
Journal: American Journal of Hematology (2022)

α-Thalassemia is one of the most important genetic modulators of sickle cell disease (SCD). Both beneficial and detrimental effects have been described previously. We use a 12-year data set on a large cohort of patients with HbSS (n = 411) and HbSC (n = 146) to examine a wide range of these clinical and laboratory associations. Our novel findings are that α-thalassemia strongly reduces erythrocyte potassium chloride co-transporter (KCC) activity in both HbSS and HbSC (p = .035 and p = .00045 respectively), suggesting a novel mechanism through which α-thalassemia induces a milder phenotype by reducing red cell cation loss. This may be particularly important in HbSC where reduction in mean cell hemoglobin concentration is not seen and where KCC activity has previously been found to correlate with disease severity. Additionally, we show that α-thalassemia not only increases hemoglobin in patients with HbSS (p = .0009) but also reduces erythropoietin values (p = .0005), demonstrating a measurable response to improved tissue oxygenation. We confirm the reno-protective effect of α-thalassemia in patients with HbSS, with reduced proteinuria (p = .003) and demonstrate a novel association with increased serum sodium (p = .0004) and reduced serum potassium values (p = 5.74 × 10-10 ). We found patients with α-thalassemia had a reduced annualized transfusion burden in both HbSS and HbSC, but α-thalassemia had no impact on annualized admission rates in either group. Finally, in a larger cohort, we report a median survival of 62 years in patients with HbSS (n = 899) and 80 years in those with HbSC (n = 240). α-thalassemia did not influence survival in HbSS, but a nonsignificant trend was seen in those with HbSC.
Macromolecular crowding transforms regenerative medicine by enabling the accelerated development of functional and truly three-dimensional cell assembled micro tissues
Authors: Andrea De Pieri, Stefanie H. Korntner, Hector Capella-Monsonis, Dimitrios Tsiapalis, Sergei V. Kostjuk, Semyon Churbanov, Peter Timashev, Alexander Gorelov, Yuri Rochev, Dimitrios I. Zeugolis
Journal: Biomaterials (2022)

Scaffold-free in vitro organogenesis exploits the innate ability of cells to synthesise and deposit their own extracellular matrix to fabricate tissue-like assemblies. Unfortunately, cell-assembled tissue engineered concepts require prolonged ex vivo culture periods of very high cell numbers for the development of a borderline three-dimensional implantable device, which are associated with phenotypic drift and high manufacturing costs, thus, hindering their clinical translation and commercialisation. Herein, we report the accelerated (10 days) development of a truly three-dimensional (338.1 ± 42.9 μm) scaffold-free tissue equivalent that promotes fast wound healing and induces formation of neotissue composed of mature collagen fibres, using human adipose derived stem cells seeded at only 50,000 cells/cm2 on an poly (N-isopropylacrylamide-co-N-tert-butylacrylamide (PNIPAM86-NTBA14) temperature-responsive electrospun scaffold and grown under macromolecular crowding conditions (50 μg/ml carrageenan). Our data pave the path for a new era in scaffold-free regenerative medicine.
FOXR2 Is an Epigenetically Regulated Pan-Cancer Oncogene That Activates ETS Transcriptional Circuits
Authors: Jessica W. Tsai, Paloma Cejas, Dayle K. Wang, Smruti Patel, David W. Wu, Phonepasong Arounleut, Xin Wei, Ningxuan Zhou, Sudeepa Syamala, Frank P.B. Dubois, Alexander Crane, Kristine Pelton, Jayne Vogelzang, Cecilia Sousa, Audrey Baguette, Xiaolong Chen, Alexandra L. Condurat, Sarah E. Dixon-Clarke, Kevin N. Zhou, Sophie D. Lu, Elizabeth M. Gonzalez, Madison S. Chacon, Jeromy J. Digiacomo, Rushil Kumbhani, Dana Novikov, J'Ya Hunter, Maria Tsoli, David S. Ziegler, Uta Dirksen, Natalie Jager, Gnana Prakash Balasubramanian, Christof M. Kramm, Michaela Nathrath, Stefan Bielack, Suzanne J. Baker, Jinghui Zhang, James M. McFarland, Gad Getz, François Aguet, Nada Jabado, Olaf Witt, Stefan M. Pfister, Keith L. Ligon, Volker Hovestadt, Claudia L. Kleinman, Henry Long, David T.W. Jones, Pratiti Bandopadhayay, Timothy N. Phoenix
Journal: Cancer Research (2022)

Abstract Forkhead box R2 (FOXR2) is a forkhead transcription factor located on the X chromosome whose expression is normally restricted to the testis. In this study, we performed a pan-cancer analysis of FOXR2 activation across more than 10,000 adult and pediatric cancer samples and found FOXR2 to be aberrantly upregulated in 70% of all cancer types and 8% of all individual tumors. The majority of tumors (78%) aberrantly expressed FOXR2 through a previously undescribed epigenetic mechanism that involves hypomethylation of a novel promoter, which was functionally validated as necessary for FOXR2 expression and proliferation in FOXR2-expressing cancer cells. FOXR2 promoted tumor growth across multiple cancer lineages and co-opted ETS family transcription circuits across cancers. Taken together, this study identifies FOXR2 as a potent and ubiquitous oncogene that is epigenetically activated across the majority of human cancers. The identification of hijacking of ETS transcription circuits by FOXR2 extends the mechanisms known to active ETS transcription factors and highlights how transcription factor families cooperate to enhance tumorigenesis. Significance: This work identifies a novel promoter that drives aberrant FOXR2 expression and delineates FOXR2 as a pan-cancer oncogene that specifically activates ETS transcriptional circuits across human cancers. See related commentary by Liu and Northcott, p. 2977
Methionine deficiency facilitates antitumour immunity by altering m<sup>6</sup>A methylation of immune checkpoint transcripts
Authors: Ting Li, Yue-Tao Tan, Yan-Xing Chen, Xiao-Jun Zheng, Wen Wang, Kun Liao, Hai-Yu Mo, Junzhong Lin, Wei Yang, Hai-Long Piao, Rui-Hua Xu, Huai-Qiang Ju
Journal: Gut (2022)

Objective Methionine metabolism is involved in a myriad of cellular functions, including methylation reactions and redox maintenance. Nevertheless, it remains unclear whether methionine metabolism, RNA methylation and antitumour immunity are molecularly intertwined. Design The antitumour immunity effect of methionine-restricted diet (MRD) feeding was assessed in murine models. The mechanisms of methionine and YTH domain-containing family protein 1 (YTHDF1) in tumour immune escape were determined in vitro and in vivo. The synergistic effects of MRD or YTHDF1 depletion with PD-1 blockade were also investigated. Results We found that dietary methionine restriction reduced tumour growth and enhanced antitumour immunity by increasing the number and cytotoxicity of tumour-infiltrating CD8 + T cells in different mouse models. Mechanistically, the S-adenosylmethionine derived from methionine metabolism promoted the N 6 -methyladenosine (m 6 A) methylation and translation of immune checkpoints, including PD-L1 and V-domain Ig suppressor of T cell activation (VISTA), in tumour cells. Furthermore, MRD or m 6 A-specific binding protein YTHDF1 depletion inhibited tumour growth by restoring the infiltration of CD8 + T cells, and synergised with PD-1 blockade for better tumour control. Clinically, YTHDF1 expression correlated with poor prognosis and immunotherapy outcomes for cancer patients. Conclusions Methionine and YTHDF1 play a critical role in anticancer immunity through regulating the functions of T cells. Targeting methionine metabolism or YTHDF1 could be a potential new strategy for cancer immunotherapy.
The association of iron‐deficiency anemia, thrombocytosis at delivery and postpartum venous thromboembolism
Authors: Xiaohua Liu, Yang Liu, Cuicui Qu, Ben Mol, Wentao Li, Hao Ying
Journal: American Journal of Hematology (2022)

Table S1 Baseline and obstetric characteristics of the study subjects Table S2 Thrombosis risk and whole blood analysis among study population Table S3 Adjusted odds ratios for associations between hemoglobin levels and venous thromboembolism and thrombocytosis Table S4 Adjusted odds ratios for associations between thrombocytosis and venous thromboembolism Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Post-vaccination infection rates and modification of COVID-19 symptoms in vaccinated UK school-aged children and adolescents: A prospective longitudinal cohort study
Authors: Erika Molteni, Liane S. Canas, Kerstin Kläser, Jie Deng, Sunil S. Bhopal, Robert C. Hughes, Liyuan Chen, Benjamin Murray, Eric Kerfoot, Michela Antonelli, Carole H. Sudre, Joan Capdevila Pujol, Lorenzo Polidori, Anna May, Prof Alexander Hammers, Jonathan Wolf, Prof Tim D. Spector, Claire J. Steves, Prof Sebastien Ourselin, Michael Absoud, Marc Modat, Prof Emma L. Duncan
Journal: The Lancet Regional Health - Europe (2022)

We aimed to explore the effectiveness of one-dose BNT162b2 vaccination upon SARS-CoV-2 infection, its effect on COVID-19 presentation, and post-vaccination symptoms in children and adolescents (CA) in the UK during periods of Delta and Omicron variant predominance.In this prospective longitudinal cohort study, we analysed data from 115,775 CA aged 12-17 years, proxy-reported through the Covid Symptom Study (CSS) smartphone application. We calculated post-vaccination infection risk after one dose of BNT162b2, and described the illness profile of CA with post-vaccination SARS-CoV-2 infection, compared to unvaccinated CA, and post-vaccination side-effects.Between August 5, 2021 and February 14, 2022, 25,971 UK CA aged 12-17 years received one dose of BNT162b2 vaccine. The probability of testing positive for infection diverged soon after vaccination, and was lower in CA with prior SARS-CoV-2 infection. Vaccination reduced proxy-reported infection risk (-80·4% (95% CI -0·82 -0·78) and -53·7% (95% CI -0·62 -0·43) at 14-30 days with Delta and Omicron variants respectively, and -61·5% (95% CI -0·74 -0·44) and -63·7% (95% CI -0·68 -0.59) after 61-90 days). Vaccinated CA who contracted SARS-CoV-2 during the Delta period had milder disease than unvaccinated CA; during the Omicron period this was only evident in children aged 12-15 years. Overall disease profile was similar in both vaccinated and unvaccinated CA. Post-vaccination local side-effects were common, systemic side-effects were uncommon, and both resolved within few days (3 days in most cases).One dose of BNT162b2 vaccine reduced risk of SARS-CoV-2 infection for at least 90 days in CA aged 12-17 years. Vaccine protection varied for SARS-CoV-2 variant type (lower for Omicron than Delta variant), and was enhanced by pre-vaccination SARS-CoV-2 infection. Severity of COVID-19 presentation after vaccination was generally milder, although unvaccinated CA also had generally mild disease. Overall, vaccination was well-tolerated.UK Government Department of Health and Social Care, Chronic Disease Research Foundation, The Wellcome Trust, UK Engineering and Physical Sciences Research Council, UK Research and Innovation London Medical Imaging & Artificial Intelligence Centre for Value Based Healthcare, UK National Institute for Health Research, UK Medical Research Council, British Heart Foundation and Alzheimer's Society, and ZOE Limited.
HINGEneering IgG for enhanced immune activation
Authors: Anja Werner, Falk Nimmerjahn
Journal: Science Immunology (2022)

Two recent studies in Science Immunology by Orr et al. and Foss et al. demonstrate that the hinge region of immunoglobulin G (IgG) is a major regulator of IgG2 and IgG3 activity, respectively. Engineering of the IgG hinge may therefore be useful for optimizing the activity of IgG subclasses.
Retraction Note to: The circRNA circAGFG1 acts as a sponge of miR-195-5p to promote triple-negative breast cancer progression through regulating CCNE1 expression
Authors: Rui Yang, Lei Xing, Xiaying Zheng, Yan Sun, Xiaosong Wang, Junxia Chen
Journal: Molecular Cancer (2022)

This article has been retracted. Please see the Retraction Notice for more detail: https://doi.org/10.1186/s12943-018-0933-7.
GFI1B acts as a metabolic regulator in hematopoiesis and acute myeloid leukemia
Authors: Longlong Liu, Pradeep Kumar Patnana, Xiaoqing Xie, Daria Frank, Subbaiah Chary Nimmagadda, Minhua Su, Donghua Zhang, Thorsten Koenig, Frank Rosenbauer, Marie Liebmann, Luisa Klotz, Wendan Xu, Jan Vorwerk, Felix Neumann, Jana Hüve, Andreas Unger, Jürgen Günther Okun, Bertram Opalka, Cyrus Khandanpour
Journal: Leukemia (2022)

Abstract Recent studies highlighted the role of transcription factors in metabolic regulation during hematopoiesis and leukemia development. GFI1B is a transcriptional repressor that plays a critical role in hematopoiesis, and its expression is negatively related to the prognosis of acute myeloid leukemia (AML) patients. We earlier reported a change in the metabolic state of hematopoietic stem cells upon Gfi1b deletion. Here we explored the role of Gfi1b in metabolism reprogramming during hematopoiesis and leukemogenesis. We demonstrated that Gfi1b deletion remarkably activated mitochondrial respiration and altered energy metabolism dependence toward oxidative phosphorylation (OXPHOS). Mitochondrial substrate dependency was shifted from glucose to fatty acids upon Gfi1b deletion via upregulating fatty acid oxidation (FAO). On a molecular level, Gfi1b epigenetically regulated multiple FAO-related genes. Moreover, we observed that metabolic phenotypes evolved as cells progressed from preleukemia to leukemia, and the correlation between Gfi1b expression level and metabolic phenotype was affected by genetic variations in AML cells. FAO or OXPHOS inhibition significantly impeded leukemia progression of Gfi1b -KO MLL/AF9 cells. Finally, we showed that Gfi1b-deficient AML cells were more sensitive to metformin as well as drugs implicated in OXPHOS and FAO inhibition, opening new potential therapeutic strategies.